We have used mouse models to show that genetically induced changes in biliary cholesterol concentrations alter dietary cholesterol absorption. In wild type C57B16 mice feeding increasing amounts of cholesterol resulted in a significant decrease in the percentage of dietary cholesterol absorbed. In these mice the decrease in the percentage of dietary cholesterol absorbed was strongly correlated with an increase in biliary cholesterol concentration. In apo E knockout mice on the same genetic background, feeding increased amounts of dietary cholesterol did not result in decreased percentage absorption of dietary cholesterol and there was no increase in biliary cholesterol concentration. Compared to nontransgenic litter mate controls, mice expressing a human HDL cholesterol levels, increased biliary cholesterol concentration and decreased percentage dietary cholesterol absorption. These experiments suggest that in mice the biliary cholesterol concentration is inversely related to the percentage of dietary cholesterol absorbed. In the current GCRC grant period we showed that feeding increased amounts of dietary cholesterol to humans resulted in a range of responses with respect to the percentage of dietary cholesterol absorbed. In response to increasing dietary cholesterol from 0.04 to 0.10% cholesterol in 18 subjects the range of change in percentage dietary cholesterol absorbed was from a decrease of 15% to an increase of 10%. We conclude from these studies that some humans are like C57B16 mice with dietary cholesterol decreasing the percentage of dietary cholesterol absorption and others are not. for the proposed GCRC grant we hypothesize that in humans, as in mice, biliary composition is a major determinant of the percentage of dietary cholesterol absorbed. Therefore, in normal volunteers we will measure the percentage of dietary cholesterol absorption and biliary composition and look for correlations. If our hypothesis is correct then candidate genes that regulate dietary cholesterol absorption and hence responsiveness to dietary cholesterol might be those that regulate biliary composition. The information resulting from this study will shed light on better diagnosis, prevention and treatment of CHD.